Gulf War Veterans' Illness: Symptom Chronicity via Interactions of Diet andLifestyle Risk Factors with the Gut Microbiome

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Project Summary/Abstract Gulf War Veterans’ Illnesses (GWVI) presents as a complex constellation of diverse symptoms that have persisted in Gulf War Veterans more than 25 years after their deployment to the Gulf region. This set of symptoms is so broad, it baffles diagnostic criteria and as a result, consideration of GWVI as a bona fide illness has progressed slowly from denial of its existence to the use of such terms as “unexplained illnesses” (used by the VA) and “multisymptom illness”. The most recent report by the Institute of Medicine Committee on Gulf War and Health (2016) concludes that GWVI is not a psychosomatic condition and sufficient evidence now exists to conclude that a causal relationship exists between being deployed to the Gulf War and the health outcomes associated with this disorder. This august Committee noted that little progress has been made in elucidating the pathological mechanisms that underlie the complex symptom set associated with GWVI and as a result, “it does not appear that a single mechanism can explain the multitude of symptoms seen in Gulf War Illness, and it is unlikely that a single definitive causal agent will be identified this many years after the war” (p. 3 of report). We agree that a single cause for all elements of GWVI is unlikely, it is possible that a single pathophysiological mechanism that could influence the diverse symptoms of GWVI, and explain their persistence, and that mechanism is a dysbiosis in the gut microbiome. The broad objectives of this project are to analyze the effects of Gulf War agents on the commensal bacteria in the gut and to determine if these interactions result in changes in the bacterial production of short chain fatty acids (SCFAs) and other bioactive small molecules produced by gut bacteria. These products of bacterial fermentation and metabolism exert numerous effects throughout the body to include the CNS. Mice will be treated with a validated mouse model of GWVI (pyridostigmine bromide plus permethrin) and the gut microbiome will be analyzed via 16S rRNA sequencing using the MiSeq platform. The effects of these same agents on SCFA production will be determined using liquid chromatography-mass spectrometry. CNS and GI disorders that are confirmed symptoms of GWVI will also be assessed. Thereafter, the effects of a high fat diet on the microbiome and SCFA production will be evaluated. Finally, a new treatment aim is proposed that will test dietary intervention and fecal microbiota transfer for their ability to restore balance in the GWVI-modified gut microbiome and to diminish the CNS and GI symptoms of this serious disorder. It is predicted that a high fat diet will magnify the effects of Gulf War agents on the microbiome and the metabolome and cause a time-dependent worsening of GWVI symptoms. Together, the application of next generation sequencing and cutting edge mass spectrometry will help fill gaps in our understanding of how Gulf War agents influence communication along the gut-brain axis. These studies may also reveal new therapeutic targets for GWVI by restoring balance in the gut microbiome through dietary and microbiota transfer interventions.